Chronic diseases are an enormous public health and economic burden, and new and growing lines of scientific evidence support a causal role for xenobiotic environmental chemicals (XECs) in the development and progression of chronic diseases, including cardio- and cerebrovascular disease (stroke). Several classes of XECs, including persistent organic pollutants and heavy metals, have been identified as increasing stroke risk, and there is emerging evidence that another class of XECs, perfluoralkyi chemicals (PFCs), may also influence stroke risk. However, there remains a knowledge gap in understanding how different PFCs may affect stroke risk and stroke outcome or how these health effects may be mediated through other conditions that causally affect stroke risk and severity. The three aims of this project are to: 1) Determine the association between PFCs and the incidence of stroke; 2) Determine the association between PFCs and stroke mortality and morbidity; and 3) Describe the natural Indirect effect of PFCs on stroke incidence and mortality and morbidity, as mediated through hypercholesterolemia and hypertension, and thyroid and immune function. This project will be conducted as an ancillary study within the REGARDS Study, an NIHfunded cohort study with an established enrollment of >30,000 people. The contribution of the work proposed here will be a systematic evaluation of the effect of multiple PFC compounds on stroke risk and stroke outcome in a diverse cohort, with a wide range of PFC exposure. The research proposed here is innovative because: 1) multiple PFC compounds will be evaluated; 2) a range PFC-related health effects and outcomes beyond mortality will be determined; 3) natural, indirect PFC-related health effects and outcomes will be determined; and 4) the present study will build upon a well-established study and so will efficiently address the study aims. It is anticipated that the results from the research proposed here will substantially advance the understanding of how PFCs affect cerebrovascular health and so will be an important progression in a continuum of research that is expected to meaningfully inform the development of public health strategies and recommendations regarding safe levels of exposure to PFCs.